16-Diazoketones of the androstane, pregnane, estrane, and 19-norpregnane series

ABSTRACT

15-Oxasteroids of the androstane, pregnane, estrane, and 19norpregnane series are useful as hormonal agents.

United States Patent [191 Rosen Mar. 18, 1975 l6-DIAZOKETONES OF THE ANDROSTANE, PREGNANE, ESTRANE, AND l9-NORPREGNANE SERIES [75] Inventor: Perry Rosen, North Caldwell, NJ.

[73] Assignee: Hoffmann-La Roche Inc., Nutley,

22 Filed: Jan. 14, 1972 211 App]. No.: 217,956

[52] US. Cl. 260/141, 260/239 AA, 260/310 R, 260/346.2 M, 260/468.5, 260/488 R,

[51] Int. Cl C07c 113/02, A6lk 17/06 [58] Field of Search 260/141, 239 AA, 346.2 M

Primary Examiner-Floyd D. Higel Attorney, Agent, or Firm-Samuel L. Welt; Jon S. Saxe [57] ABSTRACT IS-Oxasteroids of the androstane, pregnane, estrane, and l9-norpregnane series are useful as hormonal agents.

9 Claims, N0 Drawings 1 IG-DIAZOKETONES OF THE ANDROSTANE, PREGNANE, ESTRANE, AND l9-NORPREGNANE SERIES BRIEF DESCRIPTION OF THE INVENTION The present invention relates to novel compounds represented by the formula wherein R is lower alkyl of from 1 to carbon atoms; W is one of the partial formulas where R is hydrogen, lower alkyl, cycloalkyl, lower alkanoyl or aroyl; R taken independently is hydrogen; R

taken independently is a 3-hydroxy, 3-lower alkanoyloxy, 3-keto or 3-keto-A group; and R and R taken together with carbon atoms 2 and.3 ofte steroid nucleus represent a S-membered heteroaromatic ring wherein one heteroatom is attached to carbon-atom 3; R is hydrogen or methyl; and Z is one of the groups carbonyl, ketal protected carbonyl,

where Y is carbonyl or wherein R, R R R R and Z are as above.

As used throughout the specification and the appended claims, the term alkyl group refers to a monovalent radical of up to 20 carbon atoms consisting solely of carbon and hydrogen and containing no unsaturation; the term alkenyl group refers to a monovalent radical consisting solely of carbon and hydrogen of up to 20 carbon atoms containing olefinic unsaturation; the term alkynyl group" refers to a monovalent radical consisting solely of carbon and hydrogen of up to 20 carbon atoms containing acetylenic unsaturation. The term cycloalkyl group denotesa monovalent radical consisting solely of carbon and hydrogen possessing. at least one carbocyclic ring, said ring containing from 3 to 8 carbon atoms. The term alkanoyl refers to the residue of a saturated aliphatic carboxylic acid containing up to 20 carbon atoms obtained by removing the hydroxyl from the carboxyl moiety. The term alkanoyloxy group refers to the residue of a saturated aliphatic carboxylic acid containing up to 20 carbon atoms obtained by removal of the hydrogen from the carboxyl moiety. The term aroyl" refers to the residue of amonocyclic aromatic carboxylic acid obtained by removing the hydroxy] from the carboxyl moiety. The term halogen" refers to fluorine, chlorine, bromine and iodine. The term ketal protected carbonyl refers to a group which may be hydrolyzed to regenerate a carbonyl group under conventional hydrolysis conditions, such as a carbonyl protected as a di(lower alkyl)ketal, an alkylene ketal or an arylene ketal. Examples of di(lower alkyl)ketals are dimethyl ketals, diethyl ketals and so forth. Alkylene ketals are derived from 1,2 or 1,3 glycols, e.g. ethylene glycol, 1,3-propyleneglycol, 2,3- butyleneglycol and so forth. Arylene ketals are derived from catechols, e.g. phenylenel ,2-diol, alkyl-substituted-phenylene-l ,2-diols, naphthalene-1,2- or 2,3-diols, and so forth. The term heteroaromatic ring" comprehends a monocyclic ring system having aromatic unsaturation and which has at least one ring member which is not a carbon atom. The term lower," as applied to any of the foregoing groups, denotes a group having a carbon skeleton containing up to and including 8 carbon atoms.

In the formulas presented herein, the various substitutents on cyclic compounds are joined to the cyclic nucleus by one of three notations: a solid line indieating a substituent which is in the B-orientation (i.e., above the plane of the paper), a dotted line indieating a substituent which is in the q o rientation (i,e

below the plane of the pa per), a wavy linel lindicab- The preparation of a compound falling within the genus of formula llla purported to be 3B,l4-diacetoxy- 14,17-seco-D-bisnorandrostan-l7-oic acid l7-methyl ester has been described by Banerjee and Gut, J. Org.

methyl group at carbon atom 13 ofthe steriod nucleus Chem., 34, 1614 (1969). The material was prepared has been arbitrarily indicated as the B-orientation. via 8 Series Of reactions from Compound pu p rted to i.e.. the natural" steroid series, the invention is not be SB-acetoxy-l5,17-seco-D-norandrostan-l5,17-dioic to be construed as limited to the natural steroid series acid l7-methyl ester, a compound falling within the and is meant to include the corresponding unnatural genus of formula II.

and racemic series of steroids. 10 During the course of the present invention it has been The lfi-oxasteroids represented by formulas la and lb can be prepared from the corresponding carboxylic l7- oxasteroids, as depicted in Reaction Scheme A below.

discovered that both above compounds are erroneously described. It has been shown that the starting diaeid monomethyl ester was in reality 3B-acetoxy-l5.l7-

REACTION SCHEME A coon a L coon coca u on in WI II w] 5 w 03 IIIB. I R1 1 1 fz comm OOH j I on w Oti 1% IVa IIIc wherein w' is one of the partial formulas alkyl, R5 i lower alkanoyl and R, R1 and R are as 'ab ove Compounds of formula ll are known and are prepared from l7-keto-steroids by oxidative cleavage of the D-ring by methods known per se. Compounds of formula III seco-D-norandrostan-l5,17-dioic acid lS-methyl ester and the degradation product prepared therefrom 33,1- 3-diacetoxy-l 3,15-seco-D-bisnorandrostan-l S-oic acid l5-methyl ester. The preparation of 3B-acetoxy-l 5 l 7- seco-D-norandrostand 5,17-dioie acid l7-methyl ester. agreeing in physical properties with that prepared herein, was described by Fetizon and Moreau, Bull- .Soc. Chim. France, 4,385 (1969). Furthermore, it has been demonstrated that the series of reactions described by Banerjee and Gut as leading from their dioic acid dimethyl ester to their monomethyl ester acetate 5 is not operative for the analogous conversion of compound 11 to compound Illa.

According to the present invention, the degradation of a compound of formula ll to one of formula Illa is suitably effected by contacting the former with a tetra(alkanoyloxy)lead, most preferably lead tetraacetate. This reaction is generally carried out in the presence of a weak base, for example, an organic amine, preferably III wherein R is hydrogen or lower alkyl, R,, is hydrogen or lower alkanoyl and R, and W are as above, are novel and constitute part of the present invention.

pyridine. An inert organic solvent is suitably employed as a diluent, preferably hydrocarbon such as benzene or toluene. A temperature of from about 40 to about 150C. may be employed although it is generally preferred to carried out the reaction at the reflux temperature of the reaction medium.

In the next step, compound llla is hydrolyzed to the hydroxy acid of formula lllb. Where R or R" in partial formula W is lower alkanoyl or aroyl, these groups are also hydrolyzed to a hydroxy group under the reaction conditions. Suitable reaction conditions are readily suggested to one skilled in the art, and include heating a compound of formula llla with a dilute alcoholic solution of an alkali metal hydroxide, e.g. refluxing with a 3%-methanolic potassium hydroxide solution.

The hydroxy group at carbon atom 14 (and, if present, one at carbon atom 3) may then be reacylated by treatment with the desired acid chloride or anhydride to afford a compound of formula Illc. The next step is the preparation of a diazo ketone of formula IV wherein R R and W are as above.

Accordingly, the carboxyl group of the alkanoyloxy acid of formula lllc is converted to a diazo ketone moiety by treatment of an activated derivative of the acid with diazomethane. Suitable activated acid derivatives include acid halide, most preferably the acid chloride. The conversion to the diazoketone is suitably effected by contacting a solution of the acid halide in an inert organic solvent, e.g. an ether, with an excess of diazomethane, in the cold. Suitably, the reaction is carried out at about to prevent evaporation of the low boiling diazomethane.

The l4-acyloxy group of the diazo ketone of formula lVa, as well as any acylated hydroxy] groups present at carbon atom 3, are next hydrolyzed to the free hydroxy groups by alkaline saponification. Suitable saponification agents include alkali metal hydroxides, e.g. so dium hydroxide and potassium hydroxide. Saponification is suitably carried out in an inert organic solvent preferably an alcohol, e.g. methanol or ethanol. A suitable reaction temperature is about room temperature.

The diazo ketone alcohol of formula lVb is next cyclized to afford the l5-oxasteroid of formula I. This cyclization reaction is carried out in the presence of an acidic cyclization catalyst. Suitable acidic cyclization catalysts include Lewis acids, most preferably boron trifluoride and its ether complexes. The cyclization reaction is suitably performed in any anhydrous inert organic solvent; preferred organic solvents include hydrocarbons, e.g. benzene and toluene. The cyclization is preferably effected at a temperature between about 0 and about 40C., most preferably about room temperature. The reaction may be monitored by following the evolution of nitrogen, and is continued until this evolution is substantially complete.

The compounds of formula I, thus formed, may be further converted to the remaining members of the genus represented by formula I by standard transformations at the 3- and l7-positions.

Members of the subgenuses la and lb may be interconverted by a number of procedures well known in the art. For example, the A-ring aromatic I5 oxasteroids represented by formula la, may be converted to l9-nor-l5-oxastcroids, represented by formula lb where R is hydrogen by, for example, Birch reduction of the aromatic ring and subsequent hydrolysis of the resulting enol ether. In another procedure, l5-oxa-androstanes of formula lb where R is methyl may be converted to l5-oxaestrone derivatives of formula la by 'aromatization of the A-ring according to well known procedures.

Compounds of formula I having a 17-keto group may be converted to the corresponding pregnanes by addition of the requisite 2-carbon side chain at the 17- position by methods known per se for l7-keto steroids.

The conversion of the l7-keto group to other moieties represented by the substitutent Z may be accomplished in the normal manner utilized for carbocyclic l7-keto steroids, for example, by reduction of the carbonyl group to a l7B-hydroxyl function and optional acylation; or by addition of an organometallic reagent to introduce a l7a-alkyl, alkenyl or alkynyl group; and so forth. The R, function in compounds of formula lb may be modified according to standard procedures known in the art involving, for example, oxidation of the 3-hydroxy to a 3-ketone; introduction of a A- double bond; and so forth.

Compounds of formula lb wherein R: is a 3-keto or 3-keto-A function, may be converted, according to well known procedures, to steroids having a heterocyclic ring fused to the 2- and 3-positions of the A-ring. For example, 3-keto l 5-oxasteroids of formula lb may be converted, via the 2-hydroxymethylene derivatives, to the corresponding [2,3-d] or [3,2-c1-isoxazoles or [3,2-c]-pyrazoles.

Preferred compounds of the present invention are those of subgenus Ia. Particularly preferred are those wherein R is methyl, Z is carbonyl or B-hydroxymethylene and R is hydrogen or a cycloalkyl group.

The compounds of formula I exhibit hormonal activity. In particular, compounds of formula la are potent estrogens when tested in the standard estrogenic (uterotrophic) assay. In this test, the test compound is administered once daily for 3 consecutive days to a group of ten immature female rats. Uteri are removed by autopsy on the fourth day and weighed on a torsion balance and the organ ratio (mg. organ/ g. body weight) is calculated for each rat and the mean determined for each group. The percent difference from the value for the control group is computed. By way of example, l5-oxaestrone, when tested in the above assay exhibits an oral estrogenic activity approximately 12 times that of estronc, and approximately twice that of Mestranol. These compounds are thus useful in the treatment of various conditions in which estrogenic agents are indicated such as estrogen deficiencies, menopause, and the like. The compounds of formula la may also be utilized in conjunction with a progestational agent for the control of fertility.

Compounds of formula lb wherein Z is carbonyl or the group z zl C---R exhibit progestational activity in the standard Clauberg assay.

Compounds of formula 1 can be administered internally, for example, orally or parenterally, with dosages adjusted to individual requirements. Compounds of formula 1 may be administered in unit or divided dosages to make up the daily dosage regimens. The selection of the specific dosages and dosage regimens should be left to the discretion of the trained medical practitioner. By way of example, an approximate daily dosage for l5-oxaestrone in an adult human would be from about 0.01 to about 1.0 mg. per day.

The above compounds of formula I can be administered in the form of conventional pharmaceutical preparations; for example, they can be administered in conventional pharmaceutical solid or liquid forms, such as tablets, pills, capsules, solutions, suspensions, emulsions or the like. These pharmaceutical preparations can contain conventional pharmaceutical carriers and excipients such as water, talc, corn starch, polyalkylene glycol, emulsifying agents, buffering agents, agents for the adjustment of osmotic pressure, vaseline and the like. The pharmaceutical compositions described above can additionally contain other active ingredients.

The following examples serve to further illustrate the practice of the present invention and are not to be construed in any sense as limitative thereof.

EXAMPLE 1 3B-Hydroxy-l6.17-seco-l 6-norandrostan-15-(2- indoxyliden)-17-oic acid To a solution of 400 g. (1.38 mole) of isoandrosterone in 6 l. of 3% methanolic potassium hydroxide was added 275 g. (1.82 mole) of o-nitrobenzaldehyde. The mixture was stirred at room temperature under nitrogen for 18 hours, then concentrated under vacuum to a volume of approximately 2 l. The solution was then cooled and with stirring acidified with 1.2 1. of 3N hydrochloric acid. The resulting yellow precipitate was collected by filtration, washed thoroughly with water and dried. The product was then stirred in 2 l. of cold acetone, filtered and dried to give 356 g. of 3B- hydroxy-l6,l7-seco-1o-norandrostan-l5-(2'- indoxylidcnl-l7-oic acid, mp 272274.

EXAMPLE 2 3B-Hydroxy-l 6,1 7-secol 6-norandrostan-l 5-( 2 indoxyliden)-l7-oic acid l7-methyl ester To a mixture of 356 g. of 3B-hydroxy-l6,l7Seco-l6- norandrostan-l5-(2'-indoxyliden)-l 7-oic acid in 3 l. of methanol was added dropwise 40 m1. of acetyl chloride. After refluxing for four hours, themethanol was removed under reduced pressure and 2 l. of water was added to the residue. Theresulting precipitate was filtered, washed with water and dried. The productwas then dissolved in a minimum of methylene chloride and treated with Norit and dried (MgSO The mixture was filtered and the methylene chloride removed under reduced pressure. Trituration of the residue with ether afforded 325 g. of 3l3-hydroxy-l6,l7-seco-l6- norandrostan-l 5-( 2 '-indoxyliden-)-17-oic acid 1?- methyl ester, mp 258-26l.

EXAMPLE 3 EXAMPLE 4 3fi-Acetoxy-l 5 l 7-scco-D-norandrostanel 5 ,1 7-dioic acid l7-methyl ester To a suspension of 350 g. of 3B-acetoxy-l6,l7-secolo-norandrostanl 5-( 2'-indoxyliden l 7-oic acid 1?- methyl ester in 5 1. of glacial acetic acid was added dropwise 290 ml. of a aqueous chromium trioxide solution prepared by dissolving 90G chromium trioxide in ml. water. Solution soon occurred with the evolution of heat (the temperature was kept below 70 with external cooling). After stirring overnight the acetic acid was removed under high vacuum and the residue treated with 4 l. of water. The precipitate was filtered, washed thoroughly with water and dried. The product was then dissolved in benzene and the solution treated with Norit and anhydrous magnesium sulfate. The mixture was filtered and the benzene removed under reduced pressure. Trituration of the residuewith hexane afforded 255 g. of 3B-acetoxy-l5,l7-seco-D- norandrostane-l5,17-dioic acid 17-methyl ester, mp 152l58.

EXAMPLE 5 A mixture of 255 g. of 3B-acetoxy-l5,l7-seco-D- norandrostane-l5,17-dioic acid l7-methyl ester, 745 g. of lead tetra-acetate (dried in vacuo over P 0 108 ml. of pyridine and 3.8 l. of dry benzene was stirred and refluxed for seven hours. The mixture was cooled and the lead salts filtered and thoroughly washed with ether. The filtrate was washed with a 10% solution of sodium thiosulfate, 1N hydrochloric acid and then a saturated sodium chloride solution. The solution was dried (MgSO and the solvent removed under reduced pressure to give 270 g. of crude product. This material was dissolved in a minimum of benzene and washed through 1,300 g. of neutral Alumina (grade 1). Elution with 3 l. of benzene followed by l l. of a 1% ethyl acetate benzene solution afforded 215 g. of crude material. This product was then dissolved in 1,230 ml. of 3% methanolic potassium hydroxyide and stirred at for one hour. The mixture was acidified with 700 ml of 1N hydrochloric acid at 0 and the precipitate filtered and dried to give 108 g. of 3B-hydroxy-14B-acetoxy-14,l7- seco-D-bisnorandrostan-l7-oic acid 17-methyl ester, mp 127130. The methanol was removed from the filtrate under reduced pressure and the mixture extracted with methylene chloride and the resultingsolution dried (MgSO The solvent was removed under reduced pressure and the residue triturated with methanol to give 2g. of 3B-hydroxy-l4B-acetoxy-14,l7- seco-D-norandrostan-l7-oic acid l7-methyl ester, mp 126l30. A third crop of 3 g., mp 124-l28, was obtained by removing a portion of the methanol under reduced pressure. Crystallization from methanol afforded an analytical sample containing one mole of methanol, mp 134-136 [0:]D 164.76(c, 1.11%, CHCl Anal. Calcd. for C H O C, 65.59; H, 9.44

Found: C, 65.85; H, 10.09.

Acetylation with pyridine-acetic anhydride afforded I 3B, 1 4B-diacetoxyl 4, l 7seco-D-bisnorandrostan-l 7- oic acid 17-methyl ester, mp l05l06, [ot]D" 16.23(c, 0.758%, Cl-lCl Anal. Calcd. for C H O C, 66.98; H, 8.69

Found: C, 67.11; H, 8.93.

EXAMPLE 6 Anal. Calcd. for C,-,H, O.: C, 68.88; H, 9.5 Found: C, 69.16; H, 9.7

EXAMPLE 7 3B,l4,B-Dihydroxyl 6-diazo-17-oxo-l4, l6-seco-D- norandrostane To a solution of 350 ml. of acetic anhydride in 350 ml. of pyridine was added g. of 3B,l4/3-dihydroxyl4,17-seco-D-norandrostan-l7-oic acid. The solution was stirred at room temperature overnight and then poured into 6 l. of ice water. The mixture was stirred for 2 hours and then extracted with ether. The ether solution was washed with 1N hydrochloric acid and then water until neutrality. The solution was dried (MgSO,,) and the solvent removed under reduced pressure to give 83 g. of crude '3B,14B-diacetoxy-14,17-seco-D- bisnorandrostan-17-oic acid as an oil.

The crude diacetate (83 g.) was treated with ml. of oxalyl chloride and stirred at room temperature overnight. The excess oxalyl chloride was then removed under reduced pressure and the residue diluted with hexane and the solvent again removed under reduced pressure to give 85 g. of crude acid chloride.

To an ethereal solution of diazomethane prepared from 150 g. of N-methylnitrosourea was added dropwise with stirring at 0 a solution of 85 g. of the crude acid chloride in 200 ml. of ether. The solution was stirred at 0 for 2 hours and the solvent and excess di azomethane then evaporated under a stream of nitrogen to afford 3B14Bdiacetoxy-16-diazo-17-oxo-14,16- seco-D-norandrostane. This diazoketone was then added to 790 ml. of a 6% methanolic potassium hydroxide solution and stirred at room temperature for 5 hours. The reaction mixture was then cooled to 5 and the precipitate filtered to give 63 g. of 33,145- dihydroxy-l6-diazo-l7-oxo-14,16-seco-D- norandrostane, mp l45l50. Crystallization from ether-methylene chloride afforded an analytical sample, mp l54l 56, [0:]D 8.46(c, 0.9697%, CHCl Anal. Calcd. for c n n o z C, 67.47; H, 8.81

Found: C, 67.22; H, 8.91.

EXAMPLE 8 3B-Hydroxy-1S-oxa-Sa-androstan-l7-one To a suspension of 63 g. of 3B14B-dihydroxy-16- diazo-l7-oxo-l4,1-seco-D-norandrostane in 1.2 1. of dry benzene was added dropwise with stirring a solution of 15 ml. of boron trifluoride-etherate in 20 m1. of benzene. The evolution of nitrogen began immediately, and after the addition was completed 15 minutes) the reaction was stirred for an additional 10 minutes. The benzene solution was then washed with 5% sodium bicarbonate solution and the aqueous extracts backwashed with ether. The organic layers were then combined, dried (MgSO heated with Norit and then filtered. The solvent was removed under reduced pressure and the residue triturated and hexane to give 54.5 g. of 3B-hydroxy-l5-oxa-5a-androstan-17-one, mp l50. Crystallization from ether-methylene chloride afforded an analytical sample, mp l52l54, [0:]D +54,07(c, 0.505%, CHCl Anal. Calcd. for C H O C, 73.93; H, 9.65

Found: C, 73.90; H, 9.82.

Anal. Calcd. for C H O C, 71.82; H,

9.04. Found: C, 71.56; H, 8.86.

EXAMPLE 9 l 5-Oxa-5a-androstan-3 ,l 7-dione To a cooled solution of 10.0 g of 3B-hydroxy-l oxa-5a-androstan-l7-one in 100 ml. of acetone was added dropwise with stirring ml. of Jones reagent. After the addition was complete the mixture was stirred at 0 for 10 minutes. The solvent was then removed under reduced pressure and the residue treated with 300 ml. of ice water. The precipitate was filtered and washed thoroughly with water and dried. The product was then dissolved in a minimum of methylene chloride and the solution treated with Norit and filtered. The solvent was removed under reduced pressure to give 9.2 of l5-oxa-5a-androstan-3,l7-dione, mp l76180. Crystallization from ether-methylene chloride afforded an analytical sample, mp l82l85, [011D +77.39 (c, l.l798%, CHCl 4 9 Found: C, 74. 9

EXAMPLE l0 2a,4a-Dibromol 5-oxa-5 oz-androstan-3 ,1 7-dione To a solution of H35 g. of l5-oxa-5a-androstan-3, l 7- dione in 160 ml. of dry tetrahydrofuran was added 216 g. of phenyltrimethylammonium perbromide. The brominating agent quickly dissolved and after a short time phenyltrimethylammonium bromide began to precipitate. The mixture was stirred for 4.5 hours and the precipitate filtered and washed with benzene. An additional 100 ml. of benzene was added to the filtrate and the resulting solution was then washed with a 5% solution of sodium sulfite, water and then dried (MgSO The solvent was removed under reduced pressure and the residue triturated with cold ether to give 14.2 g. of 2a,4a-dibromol S-oxa-Sa-androstan-B ,l 7-dione, mp 2l2-2l4. Crystallization from methylene chlorideether afforded an analytical sample, mp 2l3215 d, [011D +l8.05 (c, 0.986l%, CHCl Anal. Calcd. for C H Br o z C, 48.24; H, 5.40

Found: C, 48.20; H, 5.50.

EXAMPLE 1 l l5-Oxa-l ,4-androstadiene-3 ,1 7-dione To a solution of 19.6 g. of lithium bromide and 19.6 g. oflithium carbonate in 200 ml. of dry dimethylformamide at 95 was added dropwise a solution of 14.7 g. of 201,401-dibromo-l 5-oxa-5a-androstan3,l 7-dione in ISO ml. of the same solvent. The mixture was stirred and maintained at 95 for 18 hours and most of the dimethylformamide was. then removed under high vacuum. To the residue was then added 200 ml. of ice water followed by 50 ml. of IN hydrochloric acid. The precipitated semi-solid was then extracted with methylene chloride and the organic layer washed thoroughly with water and dried (MgSO The solvent was then removed under reduced pressure and the residue dissolved in a minimum of methylene chloride and passed through 50 g. of neutral alumina (grade I). Elution with methylene chloride gave 9.5 g. of crude product which when triturated with ether afforded 7 g. of l5-oxa-l,4-androstadiene-3,l7 -dione, mp l8ll85. Crystallization from methylene chloride-ether afforded an analytical sample, mp ll87, [01],, +70.50(c, 0.9050%, CHCl Anal. Calcd. for C M- O C, 75.49; H, 7.74

Found: C, 75.77; H, 7.97.

EXAMPLE l2 l5-Oxa-1 ,4-androstadiene-3 ,1 7-dione-l 7-ethylene ketal A mixture of 7 g. of l5-oxa-l,4'androstadiene-3,l7- dione, 14 ml. of ethylene glycol, 0.28 g. of p-toluenesulfonic acid and 350 ml. of benzene was placed in a 500 ml. flask fitted with a Soxhlet extractor which was charged with Linde 3A molecular sieves. AFter refluxing for six hours, the reaction was cooled and washed with a 5% sodium bicarbonate solution, water, and dried (Na SO The solvent was removed under reduced pressure and the residue triturated with ether to give 6.5 g. of l5-oxa-l,4-androstadiene3,l7-dione-l7- ethylene ketal, mp l47-l50. Crystallization from methylene chloride-ether afforded an analytical sample, mp l47l 50, [04],, +6.50 (0, 0.9545%, CHCl Anal. Calcd. for C ,,H O C, 72.70; H, 7.93

Found: C, 72.76, H, 7.89.

EXAMPLE l3 l5-OXaestrone-l 7-ethylene ketal To a solution of 86.2 g. of biphenyl in 1.5 l. of dry tetrahydrofuran was added 4.35 g. of lithium wire. The mixture was stirred at room temperature for 4 hours after which time the lithium had completely dissolved. The dark blue solution was then warmed to 50 and a solution of 25.4 g. of l5-oxa-1,4-androstadiene-3,l7- dione-l7-ethylene ketal and 38.8 g. of diphenyl methane in ml. of tetrahydrofuran was added dropwise over a period of 30 minutes. The temperature was maintained at 5052 and the mixture was stirred for an additional hour. The reaction was then cooled to 0 and 45 g. of ammonium chloride was added in small portions (color changed from dark green to light brown). Small pieces of ice were then cautiously added causing the reaction to become colorless, followed by the addition of I00 ml. of ice water. The resulting two layers were separated and the aqueous solution extracted with methylene chloride. The organic layers were combined, dried (MgSO and the solvent removed under reduced pressure to give an oily residue. Hexane (800 ml.) was added and the mixture stirred until precipitation took place. The crude precipitate (25 g.) was dissolved in a minimum of methylene chloride and passed through 250 g. of silica gel. Elution with 1% ethyl acetate-benzene and ethyl acetatebenzene gave 15.5 g. of l5-oxaestrone-l7-ethylene ketal. Trituration with hexane-ether gave 12.5 g., mp 2l22l5. Crystallization from methylene chlorideether afforded an analytical sample, mp 214-2l6, [01],, +l8.99(c, 0.89% CHCl Anal. Calcd. for C, H .,O C, 72.l2', H, 7.65

Found: C, 7l.98; H, 7.53.

EXAMPLE l4 l5-Oxaestrone A solution of 12 g. of l5-oxaestrone-l7-ethylene ketal, 250 ml. of dioxane, and 20 ml. of an 8% aqueous sulfuric acid solution was stirred and refluxed for four hours. The solution was cooled, poured into 2 l. of ice water and the precipitate filtered. The product was washed thoroughly with water and air dried. The crude material was then dissolved in a minimum of 1:1 methylene chloride-tetrahydrofuran solution, dried (MgSO and heated with charcoal. The mixture was filtered and the solvent removed under reduced pressure. The resulting residue was triturated with ether to give 9.2 g. of l5-oxaestrone. Crystallization from methanol afforded two crops of product: 7.0 g. mp 254-256; 1.4 g., mp 252254. Crystallization from methanol of the first crop afforded an analytical sample, mp 255-256, [11],, +l08.45(c, 0.876%, ChCl Anal. Calcd. for C H O C, 74.97; H, 7.40. Found: C, 75.28; H, 7.84.

EXAMPLE l5 Anal. Calcd. for C H O C, 74.42;

H, 8.08 Found: C,7 H 8 9.

EXAMPLE l6 l5-Oxa-3-methoxyl 9-nor-l 7a-pregna l ,3,5( 10 trien-ZO-ynl 7-ol To a dioxane solution (48 ml.) saturated with acetylene at 0 was added 4.8 g. oflithium acetylide-ethylene diamine followed by the dropwise addition (30 min.) of 0.8 g. of l5-oxaestrone dissolved in 16 ml. of dry dioxane. During the addition and for 40 minutes thereafter acetylene was bubbled through the reaction mixture. The reaction was then stirred at room temperature for 3.5 hours after which time 100 ml. of 20% hydrochloric acid was added slowly with stirring at 0. The mixture was then extracted with ether, and the ether solution washed with 0.lN hydrochloric acid, water, and then dried (MgSO The solvent was then removed under reduced pressure to afford l5-oxa-3-hydroxy-l9-norl7a-pregna-l ,3,5( l0)-trien-20-ynl 7-ol. This was treated directly for 3 days with an ethereal solution of diazomethane. When the reaction was complete (tlc) the solvent and excess diazomethane were blown off by a stream of nitrogen and the resulting product dissolved in a minimum of benzene and passed through 1 g. of silica gel. Elution with benzene afforded 0.75 g. of crude material which when triturated with hexane gave 0.57 g. of l5-oxa-3-methoxy-l9-nor-17a-pregna-1 ,3,5( 10)- trien-20-yn-l7-ol, mp ll2l24. Drying at /O.l mm for 18 hours afforded 0.5 g., mp l40l42, [(11 0 (c, 0.8725%, CHCl Anal. Calcd for C.,,,H.,,o,; C, 76.64; H, 8.04

Found: C, 76.74; H, 7.80.

EXAMPLE 17 3,8, l 7B-Dihydroxyl 7a-methyl-l 5-oxa-5a-androstane To a solution of 2 g. of 3B-hydroxy-l5-oxa-5aandrostanl 7-one dissolved in 20 ml. of dry tetrahydrofuran was added dropwise at 70, 10.8 ml. of a 1.9 molar solution of methyl lithium in ether. The resulting thick gelatinous mass was stirred for 10 minutes and then added to ml. of a 5% aqueous solution of sodium dihydrogen phosphate. The mixture was then extracted with methylene chloride, the solution dried (MgSO and the solvent removed under reduced pressure. The residue was then crystallized from acetone to give 1.5 g. of 3,8,17B-dihydroxy-l7a-methyll5-oxa-5a-androstane, mp 227229, [01],, l3.58(c, 0.5303%, CHCl Anal. Calcd. for C H O C, 73.98; H, l0.46

Found: C, 73.67, H, l0.76.

EXAMPLE l8 l7B-l-lydroxy-l 7or-methyl-l 5-oxa-5a-androstan-3-one To a suspension of 1.8 g. of crude 3B,l 7B-dihydroxyl7a-methyl-l 5-oxa-5oz-androstane in 20 ml. of acetone 7 was added with stirring at 0 2 ml. of Jones reagent.

Dissolution soon occurred and after 10 minutes the oxidation was found to be complete (tlc). The solution was then poured into 100 ml. of ice water, and the reaction mixture extracted with methylene chloride after saturation of the aqueous solution with sodium chloride. The organic layer was dried (MgSO.,) and the solvent removed under reduced pressure to give 1.5 g. of l7B-hydroxyl 7a-methyl-l 5-oxa-5a-androstan-3-one.

Crystallization from methylene chloride-ether afforded an analytical sample, mp l96l98, [a],, +6.43(c, O.9646%, CHCl Anal. Calcd. for C H O C, 74.47; H, 9.8

Found: C, 74.73; H, 10. 8.

EXAMPLE 19 15-Oxa-l7B-hydroxy-17a-methyl-5a-androstane[3 ,2- c]pyrazole A solution of 2.5 g. of 17B-hydroxy-17a-methyl-15- oxa-a-androstan-3-one, 0.84 g. of sodium methoxide, 4.6 ml. of ethyl formate and 25 ml. of pyridine was stirred under nitrogen for 18 hours. The mixture was then poured into 300 ml. of ice water containing 46 ml. of glacial acetic acid. The resulting precipitate was filtered, washed with water and dissolved in a small amount of ether. The cloudy solution was dried (MgSO and thesolvent removed under reduced pressure'to give 2 g. of white crystalline (2-formyl-17B- hydroxy-17a-methyl-l 5-oxa-5a-androstan-3-one), mp 2621-269; AH 285 (67,430).

A solution of 2 g. of the formylated material, 50 ml. of absolute ethanol and 0.48 ml. of hydrazine hydrate (85%) was refluxed for 1 hour. The ethanol was removed under reduced pressure and the residue triturated with ether to give 1.8 g. of -oxa-17B-hydroxyctnthylr5 5at lmlatlfiZZiQBEY a Q Q- Q xst i ia i tion from chloroform afforded an analytical sample, mp 175 d, [01],, +31.45(c, 0.9826%, CH OH).

Anal. Calcd. for C H N O C, 72.69; Found: C, 72.86;

EXAMPLE 20 15-Oxaestrone cyclopentyl ether A solution of 0.29 g. of l5-oxaestrone, 3 ml. of absolute ethanol, 1 ml. of cyclopentyl bromide and 1.5 ml. of a lithium methoxide-methanol solution (10.23%, sp gr 0.853) was refluxed for 18 hours. The solution was then poured into 50 ml. of water and the mixture extracted with methylene chloride. The methylene chloride solution was then dried (MgSO and most of the solvent removed under reduced pressure. The residue was then passed through a 3 g. of netural alumina (grade 1 and the product crystallized from methylene chloride-ether to give 0.2 g. of 15-oxaestrone cyclopentyl ether, mp l98-201, [01],, +117.85 (c, 1.125%, CHCl Anal. Calcd. for C H O C, 77.61;

H, 8.29 Found: C, 77.75, H, 8.58.

EXAMPLE 21 l6-norestra-l ,3,5( l0)-trien-l 5-(2 -indoxyliden)-l 7- oic acid l7-methyl ester, mp 259260 (dec. according to the procedure of example 2.

EXAMPLE 22 3-Methoxy-l6,17-seco-16-norestra-l,3,5(10)-trien- 15-(2'-indoxyliden)-l7-oic acid l7-mcthyl ester was converted to 15-oxaestrone 3methyl ester according to the procedures in examples 4 through 8 via the following intermediates:

3-methoxy-l5,17-seco-D-norestra-l ,3 ,5( l0)-tricn- 15,17-dioic acid l7-methyl ester,

3-methoxy-14B-acetoxy-l4,17-seco-D-bisnorestra- [,3,5( l0)-trien-17-oic acid l7-methyl ester,

3-methoxyl 4B-hydroxyl 4, l 7-seco-D-bisnorestra- 1,3,5(10)-trien-17-oic acid,

3-methoxy-14B-acetoxy-14,17-seco-D-bisnorestral,3,5( l0)-trien-l 7-oic acid,

3-methoxy-l4B-acetoxy-16-diazo-17-oxo-l4,l6- seco-D-norestra-1,3,5(10)-triene, and

3-methoxy-14/3-hydroxy-16-diazo-17-oxo-14,16- seco-D-norestra-l ,3,5( lO)-triene.

EXAMPLE 23 Estrone was converted to l5-oxaestrone according to the procedures in examples 1 through 8 via the following intermediates:

3-hydroxy-16,17-seco-l6-norestra-1,3,5(10)-trie nl5-(2'-indoxy1iden)-17-oic acid,

3-hydroxy-l6,17-seco-l6-norestral ,3 ,5( 10 )-trien- 15-(2-indoxyliden)-l7-oic acid l7-methyl ester,

3-acetoxy-16,17-seco-l6-norestra-1,3,5(10)-trien- 15-(2'-indoxyliden-l7-oic acid l7-methyl ester,

3-acetoxy-l5,17-seco-D-norestra-l,3,5( l0)-trien- 15,17-dioic acid l7-methyl ester,

3 ,14B-diacetoxy-l4,1 7-seco-D-bisnorestra- 1,3,5(10)-trien-l7-oie acid 17-methyl ester,

3-hydroxy-l4B-acetoxy-l4,17-seco-D-bisnorestra- 1,3,5( l0)-trien-17-oic acid l7-methyl ester,

3 ,14B-dihydroxy-l4,17-seco-D-bisnorestral,3,5( l0)-trien-l7-oic acid.

3 l 4,8-diacetoxyl 4,1 7-seco-D-bisnorestral,3,5( l0)-trien-17-oic acid,

3,14B-diacetoxy-l6-diazo-l7-oxo-14,16-seco-D- norestra-l ,3,5( l0)-triene, and

3,14B-dihydroxy-l6-diazo-17-oxo-l 4,16-seco-D- norestra-1,3,5 (10)-triene.

EXAMPLE 24 l5-Oxaestr0ne 3-methyl ether was converted to 15-oxa-19-nortestosterone, according to well known procedures for the conversion of estrone 3-methyl ether to l9-nortestosterone, i.e. lithium-ammonia reduction to 3-methoxy-l 5-oxa-estra-2,5( 10)dien- 1 73-01 followed by strong acid hydrolysis. l5-oxa-19-nortestosterone was converted to l5-oxa-l9-norandrost 4- en-3,17-dione by oxidation with chromium trioxide.

EXAMPLE 25 l5-Oxaestrone 3-methyl ether was converted to 1S-oxa-l9-norprogesterone, according to the procedure in US. Pat. No. 3,385,849, via the following intermediates:

3-methoxy-l5-oxa-l9-norpregna-1,3,5( l0),17(20)- tetracne,

3-methoxy-15-oxa-l9'norpregna-1,3 ,5(10)-trien-20- ol,

3-mcthoxy-l 5-oxal 9-norpregna-2,5( l0 )-dien--ol, and

l5-oxa-l9-norpregn-4-en-3-on-20ol EXAMPLE 26 wherein R is lower alkyl of from l to 5 carbon atoms, R is hydrogen or lower alkanoyl and W is wherein R is hydrogen, lower alkyl or lower alkanoyl R" is hydrogen or lower alkanoyl and R is hydrogen or methyl.

2. The compound of claim 1 wherein R is lower alkanoyl.

3. The compound of claim 2 which is 3B,l4B- diacetoxyl 6-diazo-l 7-oxol 4, l 6-seco-D- norandrostane.

4. The compound of claim 2 which is 3-mcthoxyl4B-acetoxy-l6-diazo-l 7-oxo-14,16-scco-D-norestral,3,5( lO)-triene.

5. The compound of claim 2 which is 3,1413- diacetoxy-l6-diazo-l 7-oxo-14,16-seco-D-norestral,3,5( lO)-triene.

6. The compound of claim 1 wherein R is hydrogen.

7. The compound of claim 6 which is 38,1413- dihydroxy-l 6-diazol 7-oxol 4, l 6-seco-D- norandrostane. Y

8. The compound of claim 6 which is 3-methoxy l4- hydroxyl 6-diazo-l 7-oxol 4,1 -seco-D-norestral,3,5( l0)-triene.

9. The compound of claim 6 which is 3,143- dihydroxyl 6-diazol 7-ox0 l 4, l 6-seco-D-norestra- 1 ,3,5( l0)-triene. 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 wherein R5 is lower alkanoyl.
 3. The compound of claim 2 which is 3 Beta ,14 Beta -diacetoxy-16-diazo-17-oxo-14,16-seco-D-norandrostane.
 4. The compound of claim 2 which is 3-methoxy-14 Beta -acetoxy-16-diazo-17-oxo-14,16-seco-D-norestra-1,3,5(10)-triene.
 5. The compound of claim 2 which is 3,14 Beta -diacetoxy-16-diazo-17-oxo-14,16-seco-D-norestra-1,3,5(10)-triene.
 6. The compound of claim 1 wherein R5 is hydrogen.
 7. The compound of claim 6 which is 3 Beta ,14 Beta -dihydroxy-16-diazo-17-oxo-14,16-seco-D-norandrostane.
 8. The compound of claim 6 which is 3-methoxy-14-hydroxy-16-diazo-17-oxo-14,16-seco-D-norestra-1,3,5(10)-triene.
 9. The compound of claim 6 which is 3,14 Beta -dihydroxy-16-diazo-17-oxo-14,16-seco-D-norestra-1,3,5(10)-triene. 